Lipid Disorders: Diagnosis, Management, and Controversy

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[edit] Lipid Disorders: Diagnosis, Management, and Controversy

David A. Halle

Joseph Loscalzo

Coronary heart disease (CHD) is the leading cause of death in the United States, with a prevalence that is equally distributed between men and women. Cholesterol is a well-known major modifiable risk factor for CHD, and several large prospective studies have convincingly demonstrated that lowering cholesterol improves CHD risk. This finding has broad- ranging implications for public health, as well as for the individual patient, that both society and the primary care physician need to address. Since there is not universal agreement among lipid experts, the primary care physician must make judicious decisions about whom to treat, with what therapies, and how to monitor the response to therapy. To understand the general principles of evaluation and management of lipid disorders, it is first necessary to review basic lipid metabolism.

[edit] LIPID METABOLISM

There are three major forms of lipid found in mammals: phospholipids, triglycerides, and cholesterol. Each has its own unique structure and purpose, with the liver playing a central role in the synthesis and metabolism of all classes.

[edit] Phospholipids

Phospholipids are synthesized in all cells, but most are produced in the liver and, to a lesser extent, the intestinal mucosa. These amphipathic molecules not only play vital roles in cellular membrane structure and in myelination of nerve fibers, but are also important in solubilizing more hydrophobic lipids, such as cholesterol and cholesteryl ester.

[edit] Triglycerides

Triglycerides are essentially the storage form of free fatty acids utilized as an energy source. They are retained primarily in the liver and in adipose tissue, where they are stored until needed and then released through the activity of lipases. Triglycerides consist of three fatty acid molecules esterified to one molecule of glycerol. Fatty acids differ in chain length and the number of double bonds between carbon atoms. The more double bonds there are, the more unsaturated the fat.

Hydrogenation is the process used in the food industry to convert the double bonds into single bonds with the addition of hydrogen atoms to the carbon atoms. This chemical process leads to saturation of fatty acids, and tends to solidify the fat at room temperature. The process of hydrogenation can also change the isomer configuration around a double bond from a cis to a trans configuration. The consumption of trans-unsaturated fatty acids, when compared to cis-unsaturated fatty acids, has been associated with a more atherogenic profile and increased CHD.^[1]

Dietary triglycerides contain saturated, monounsaturated, and polyunsaturated fatty acids. Saturated fatty acids have the greatest impact on elevating low-density lipoprotein (LDL) cholesterol.^[2] They are also the predominant fatty acid consumed in the American diet (15% of total calories) and are derived from meat products, dairy products (including eggs), and vegetable oils (Box 71-1).

Monounsaturated fatty acids are derived from vegetable and animal fats, and have a modest LDL cholesterol-lowering effect. Oleic acid is a monounsaturated fatty acid and a main component of olive oil. The low prevalence of CHD in Mediterranean populations, who consume large amounts of olive oil, has prompted its recommendation as a dietary replacement for saturated fatty acid.^[3]

Polyunsaturated fatty acids (PUFAs) are the only essential fatty acids of the three groups because they are not synthesized by mammals de novo and need to be obtained from plants and cold-water fish. They are required for various metabolic activities, including the synthesis of arachidonic acid and prostaglandins. There are two principal groups of polyunsaturated fatty acids: the omega-6 fatty acids, and the omega-3 fatty acids.

Linoleic acid, the major omega-6 fatty acid, was considered to be the preferential fatty acid for replacement of saturated fatty acid consumption. However, this is now questioned because the long-term safety of a diet high in linoleic acid is not known. In contrast, the safety of oleic acid, a staple in the Mediterranean diet for a considerable amount of time, is not questioned. The consumption of linoleic acid should not exceed 7% of total calories. Omega-3 fatty acids, which are present in high concentrations in fish, can improve the lipid profile and inhibit platelet aggregation, which may reduce the risk of intravascular thrombosis. In one study, the consumption of omega-3 fatty acids decreased triglycerides by 30% compared with fasting levels in patients without CHD.^[4] The benefits of lowering CHD risk are theoretic and have not been proven in large clinical trials.

[edit] Cholesterol

Cholesterol is a critical lipid component of all cell membranes. In addition, it is a metabolic precursor for steroid hormones (adrenocortical hormones, estrogens, progesterone, and testosterone), and is used in the synthesis of cholic acid in bile. Cholesterol is obtained through dietary sources (exogenous pathway) or synthesized de novo (endogenous pathway). The exogenous pathway involves the absorption of dietary cholesterol through the gastrointestinal tract (250 to 500 mg per day). Endogenous synthesis, however, is the main source of cholesterol (600 to 1000 mg per day). Synthesis of cholesterol begins with the conversion of acetate into 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA), which is then converted to mevalonic acid by HMG CoA reductase. This is the rate-limiting step in the overall synthesis of cholesterol, and inhibition of this enzyme decreases cholesterol synthesis.

[edit] LIPID TRANSPORT

All lipids are transported in the circulation within large particles that also include a number of types of apoproteins. Together, these molecular assemblies form what are known as lipoproteins. Lipoproteins provide a means to solubilize their relatively hydrophobic components and, through specific apoproteins, engage in unique metabolic reactions. Clinically important lipoproteins are classified into six main categories: chylomicron, very low-density lipoprotein (VLDL), chylomicron remnant, intermediate-density lipoprotein (IDL), LDL, and high-density lipoprotein (HDL) (Table 71-1). They are named based on their relative protein content and its effect on particle density, with the least dense and most lipid-rich being chylomicrons and the most dense and least lipid-rich being HDL. Each lipoprotein has its own unique route of synthesis and functions.

Table 71-1 Lipoprotein Classes and Composition

[edit] Chylomicrons

On entering the gastrointestinal tract, phospholipids, triglycerides, and cholesterol are transported across the intestinal mucosa and assembled into chylomicrons (Fig. 71-1). Chylomicrons are triglyceride-rich particles that are absorbed in the intestinal lacteals where they enter the lymphatic system and, eventually, the bloodstream. Once in circulating blood, chylomicrons enter capillary beds in adipose tissue and liver where endothelial lipoprotein lipase acts to hydrolyze a majority of the triglycerides. Depending on the tissue, triglycerides may be stored for energy in adipocytes, undergo lipolysis so that free fatty acids can be used for immediate fuel in muscle, or undergo oxidation in the liver. The modified particle that remains, the so-called chylomicron remnant, is then removed from the circulation by the liver.

Figure 71-1 Pathways of lipid metabolism. The exogenous pathway (left) describes the absorption of metabolism of fats ingested from dietary sources. Absorbed fats form chylomicrons, which move from lymph into the bloodstream where insulin activates lipoprotein lipase to release fatty acids for use by muscle or fat. The endogenous pathway (right) depicts formation of lipoproteins within the liver followed by metabolism in other parts of the body and return to the liver. After hepatic synthesis of VLDL with apo C, E, and B-100, lipoprotein lipase is stimulated in the same fashion as the exogenous pathway. The remnant IDL is either taken up by the liver through apo E receptors or further metabolized to LDL. LDL circulates through the periphery and is taken up at the liver by the LDL receptor. Although there is essentially no feedback mechanism within the exogenous pathway, the endogenous pathway can exert feedback inhibition through the receptors on the cell service. In the reverse transport pathway, free cholesterol is taken up by nascent HDL in peripheral tissues and transferred to apo E–containing lipoproteins which can then be taken up by apo I receptors in the liver. Direct hepatic uptake of HDL may also exist. (From Frishman WH, et al: Medical management of lipid disorders, Mount Kisco, NY, 1992, Futura.)

[edit] Very Low-density Lipoprotein

Lipids taken up as chylomicron remnants are reassembled with apoproteins synthesized by the liver and released in the form of VLDL. VLDL is also reasonably triglyceride-rich and is metabolized by capillary endothelial lipoprotein lipase to release free fatty acids for utilization or storage. The remaining VLDL remnants, which include small VLDL, β-VLDL, and IDL, are then either taken up by the liver or further metabolized to LDL.

[edit] Low-density Lipoprotein

LDL is the main cholesterol-containing lipoprotein and is the primary source of cholesterol delivery to peripheral tissues. LDL contains unique apoproteins (specifically apoproteins B and E) for which peripheral cells have specific receptors. The classic LDL receptor is responsible for the uptake of LDL by all nucleated cells. Approximately 75% of LDL receptors are found in the liver, and the expression of this receptor is feedback-regulated: increasing LDL concentration is associated with a reduction in LDL receptor density. A rising intracellular concentration of LDL also leads to negative feedback inhibition of HMG CoA reductase activity, thereby decreasing endogenous cholesterol production.

There are several consequences of increased LDL in the vasculature. First, when intravascular LDL increases, there is increased LDL entry into the intima of the artery wall. Second, LDL may be oxidized by smooth muscle cells and endothelial cells. Third, monocytes enter the vessel wall where they accumulate and take up the oxidized LDL via a unique class of unregulated receptors, the scavenger receptor class. This process leads to the formation of the lipid-laden macrophage or foam cell. Fourth, the lipid-laden macrophages accumulate to form the first visible sign of atherosclerosis—the fatty streak.

[edit] High-density Lipoprotein

HDL is the reverse transport lipoprotein and is responsible for taking cholesterol from the periphery back to the liver, where it may be used in the production of cholic acid and excreted in the form of bile salts. Increases in HDL are associated with a decreased risk of coronary heart disease.^[5]

[edit] FACTORS INFLUENCING LIPID METABOLISM

[edit] Environmental

Dietary habits have some influence on serum cholesterol concentrations. A common misconception among patients, however, is that limiting dietary cholesterol intake will have a significant effect on lowering serum cholesterol levels. Reducing dietary cholesterol intake from standard Western dietary levels (approximately 300 mg daily) by as much as one third has only a modest effect, at best, on serum cholesterol concentrations. Exchanging polyunsaturated fats for saturated fats, in contrast, can have a marked effect on serum cholesterol levels. The Hegsted equation illustrates the relationship among the dietary consumption of cholesterol, saturated fats, and polyunsaturated fats on total serum cholesterol:

Change in total serum cholesterol=

2.10 (ΔS) − 1.16 (ΔP) + 0.0670 (ΔC)^[2]

ΔS and ΔP are the changes in the dietary content of saturated and polyunsaturated fatty acids in mg/dl, respectively. ΔC is the change in dietary cholesterol consumption expressed in mg/1000 kcal. As can be ascertained from this equation, a diet high in saturated fat contributes more of an effect than dietary cholesterol on the total serum cholesterol levels. This more profound effect of saturated fat has been attributed to its ability to alter (reduce) LDL receptor activity, thereby leading to elevated LDL cholesterol. With this knowledge and the fact that saturated fat is quite atherogenic, primary care physicians should counsel patients on modifying their dietary habits accordingly.

Lipid profiles, in general, are also negatively influenced by corticosteroids, anabolic steroids, cimetidine, thiazide diuretics, and β-blockers without intrinsic sympathomimetic activity. The importance of these factors in altering the course of CHD, however, has yet to be definitively proved.

[edit] Receptors, Enzymes, and Surface Proteins

Defects of certain receptors, enzymes, and apoproteins can lead to the elevation of lipids and lipoproteins. This more molecular understanding of dyslipidemias has led to a new empirical classification replacing the phenotypic classification of Fredrickson, Levy, and Lees (Types I-V) (Table 71-2).

Table 71-2 Primary Dyslipidemias and Their Treatment

Familial hypercholesterolemia (Type IIa) is the best studied molecular cause for hyperlipidemia, but it is not that common (minimal heterozygote frequency of 1:500). Manymutations in the LDL receptor gene can lead to this phenotype, but do so through different mechanisms. The basis for the resulting hyper-LDL-emia ranges from reduced affinity of the LDL-receptor for LDL to defective internalization of the LDL ∼ LDL-receptor complex. Importantly, the atherogenic risk of hyper-LDL-emia is a consequence of enhanced LDL oxidation and uptake by the scavenger receptor in monocytes and vascular cells in a process that is not feedback inhibited.

Familial combined hyperlipidemia (Type IIb) occurs in approximately 1% of the U.S. population. Several abnormalities caused by genetic or secondary factors have been attributed to this phenotype. Increased accumulation of apo B-100 will increase the levels of apo B–containing lipoproteins (VLDL and LDL). Overproduction of VLDL and LDL, abnormal clearance of these lipoproteins, and decreased lipoprotein lipase activity can also contribute to this disorder.

Familial dysbetalipoproteinemia (Type III) is characterized by accumulation of β-VLDL (remnantlike lipoprotein) in the serum because an abnormal isoform of apo E slows hepatic clearance. The remnants circulate longer, accumulate cholesteryl esters, and are readily taken up by macrophage receptors to promote atherosclerosis. This is a rare disorder that may have important physical signs that suggest the diagnosis. These include yellow discoloration of palmar and digital creases by xanthomatous deposits (palmar xanthomas) and premature atherosclerosis.

A defect in lipoprotein lipase or one of its cofactors (insulin or apo C-II) will lead to hypertriglyceridemia. A defect in this enzyme is responsible for familial hypertriglyceridemia (Type IV), which is an autosomal dominant disorder found in 5% of all patients who sustain a myocardial infarction under the age of 60.

Chylomicronemia is diagnosed by the finding of chylomicrons in a fasting serum sample. Chylomicrons are not known to be atherogenic, but elevated levels are often seen in the setting of increased triglycerides, which have been linked to CHD risk (see Controversies and Future Considerations). Elevated triglyceride production has been associated with excessive alcohol consumption and obesity. Impaired activity of lipoprotein lipase can also cause elevated levels of triglycerides. This state can be acquired, as found in the endothelial dysfunction accompanying type II diabetes mellitus. Under these circumstances, secondary hyperchylomicronemia (Type V) occurs, which is manifest as greatly elevated serum triglycerides (>1000 mg/dl), and can be accompanied by lipemia retinalis and eruptive xanthomas. An absolute deficiency in lipoprotein lipase can also be inherited as an autosomal recessive trait, and is a cause of primary hyperchylomicronemia (Type I).

Low levels of HDL (hypoalphalipoproteinemia) can be primary or secondary in origin. Primary hypoalphalipoproteinemia is seen in the setting of normal cholesterol and triglyceride levels, and has been associated with genetic mutations in apoprotein A-I and lecithin:cholesterol acyltransferase (LCAT).^[6] Secondary hypoalphalipoproteinemia usually coexists with elevated triglyceride levels and is associated with obesity, tobacco use, reduced physical activity, and hypertriglyceridemia. HDL levels are also negatively influenced by progestins, corticosteroids, anabolic steroids, cimetidine, thiazide diuretics, and β-blockers without intrinsic sympathomimetic activity.

The mechanisms of HDL metabolism are not fully understood. Thus optimal drug therapy tailored to this condition is lacking. The approach to the patient with low HDL is to modify the risk factors that may be influencing it. Estrogen and exercise will increase HDL modestly. Hypertriglyceridemia is present in up to one half of individuals with low HDL, and therapy targeted at lowering triglycerides will be beneficial in this subset of patients.

[edit] Other Disease States

Various disease states are secondarily responsible for altered lipid metabolism, as well, including hypothyroidism, which leads to hypertriglyceridemia and hypercholesterolemia, and diabetes mellitus, which leads to hypertriglyceridemia. Obstructive liver disease causes increased serum cholesterol by blocking cholesterol excretion. The nephrotic syndrome may also increase LDL production by stimulating synthesis of lipoproteins and triglycerides as a partially compensatory mechanism by which to maintain plasma oncotic pressure in the face of hypoalbuminemia.

[edit] CHOLESTEROL AND THE RISK OF CHD

The risk of CHD directly correlates with total serum cholesterol concentration. Serum cholesterol levels beginning in the range of 150 to 180 mg/dl in men as young as 20 years old have been associated with a low subsequent CHD risk, but the risk increases in a curvilinear fashion (Fig. 71-2).^[7] The steepest part of the curve, where CHD risk is compounded, occurs above total cholesterol levels of 240 mg/dl. In middle age, treatment trials have shown that for every 1% reduction in total cholesterol levels, the risk of CHD is lowered by 2% to 3%.^[8] Women have half the risk of developing CHD compared with men at any given cholesterol level.

Figure 71-2 Age-adjusted 6-year coronary heart disease (CHD) death rate (per 1000 men screened for Multiple Risk Factor Intervention Trial) according to serum cholesterol. (From Martin MJ, et al: Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men, Lancet 11:933-936, 1986.)

It is now recognized that the association between CHD risk and increasing total serum cholesterol levels is a direct consequence of the elevated LDL cholesterol component of the total cholesterol pool. HDL cholesterol is an independent risk factor for CHD, but is inversely related to CHD risk. When lipid profiles have been analyzed in men with CHD, 20% of them have a total cholesterol less than 200 mg/dl but a low HDL level of less than 35 mg/dl. From these observations, the National Cholesterol Education Program Adult Treatment Panel II (NCEP II) advocates that both total cholesterol and HDL cholesterol should be measured simultaneously for the screening and risk assessment of patients.^[9]

Elevated levels of HDL cholesterol appear to offset risk attributed to elevated LDL cholesterol levels disproportionately. The precise mechanism by which HDL offers protection against atherosclerosis is not known. An inverse correlation exists between HDL levels and concentration of apo B–containing lipoproteins. Thus some of the increased risk attributed to low HDL levels may actually be a consequence of elevated levels of other lipoproteins. HDL, by serving as a reverse cholesterol transporter, may slow atherosclerotic progression by removing cholesterol from the arterial wall.^[10] HDL may also prevent the oxidation and aggregation of LDL within the arterial wall.

Framingham Study data initially revealed the reduction in CHD risk attributed to HDL.^[5] Individuals with high total cholesterol concentrations in association with HDL cholesterol levels greater than or equal to 60 mg/dl have no increased risk for CHD, a lipid profile common in postmenopausal women on estrogen therapy. Accordingly, the NCEP II supports subtracting one CHD risk factor when an individual's HDL cholesterol is greater than or equal to 60 mg/dl.

The accuracy of measuring serum cholesterol can be quite variable, with reported coefficients of variation as great as 14%. Levels depend on patient stress, collection technique, and variability in laboratory assay methods, among other factors. Cognizant of this variation, the Centers for Disease Control and Prevention has established a national standardization program to minimize variations both within and between laboratories, and many hospital laboratories participate in this program. Of the three lipids commonly measured, total cholesterol varies less than HDL cholesterol and triglycerides. When more precision is required, the average of two or more different measurements should be used.

[edit] THE EFFICACY OF PRIMARY PREVENTION

The importance of screening for dyslipidemias is supported by overwhelming evidence that cholesterol lowering in patients with high cholesterol reduces the risk of CHD and, in patients with documented CHD, improves morbidity and mortality. The benefit of identifying and treating patients for primary prevention of CHD stems from four large prospective trials, each using different agents: the World Health Organization Cooperative Trial (1978) with clofibrate, the Lipid Research Clinics Coronary Primary Prevention Trial (1984) with cholestyramine, the Helsinki Heart Study (1987) with gemfibrozil, and the West of Scotland Coronary Prevention Study (1995) with pravastatin.^{[11][12][13][14]} These trials were similar in design, with the enrollment of middle-aged men who had elevated cholesterol levels (means ranging from 246 to 289 mg/dl) and no CHD. The incidence of cardiac events was reduced by 19% to 34% over a 5-to 7-year period. The West of Scotland Coronary Prevention Study was the only trial of the four to show a reduction in all-cause mortality (22%).

AFCAPS/TexCAPS (1998) is a more recent primary prevention study conducted on 6605 men and women with average total cholesterol levels (mean 228 mg/dl) and low HDL cholesterol (mean 40 mg/dl for women and 36 mg/dl for men).^[15] Lovastatin of 20 or 40 mg daily was compared with placebo. After a mean follow-up of 5 years, cardiovascular events were significantly reduced (37%) in the lovastatin group. With the results of these latter two trials, lipid experts have attributed these benefits to the statin (HMG CoA inhibitor) class of lipid-lowering agents as a whole. They are more effective in lowering LDL cholesterol and their side effect profile makes them more tolerable for patients than the agents used in the earlier primary prevention trials.

[edit] THE EFFICACY OF SECONDARY PREVENTION

Improving dyslipidemia in patients with documented CHD also confers a marked benefit in preventing recurrent events (secondary prevention). One of the more notable trials to show the significant benefits for secondary prevention was the Scandinavian Simvastatin Survival Study (1994).^[16] This prospective trial showed a decrease in cardiac mortality of 42% and in all-cause mortality of 30% over 5.4 years in 4444 patients with preexisting CHD. Importantly, patients treated with cholesterol-lowering therapy for secondary prevention derived much greater benefit than those treated for primary prevention after adjusting for the cholesterol level. This observation suggests that future approaches to identifying those individuals without clinical CHD and with hypercholesterolemia at greatest risk for a CHD event will be important for optimizing therapy among this broad population of individuals. A more recent notion is that the percent reduction of LDL may be more important than the absolute change in LDL concentration.^[17]

The question of how much benefit, if any, accrues to CHD patients with average cholesterol levels was elucidated by the Cholesterol and Recurrent Events (CARE) trial (1996).^[18] This trial enrolled over 4000 post–myocardial infarction patients with mean total serum cholesterol of 209 mg/dl and LDL cholesterol of 139 mg/dl, then subjected them to treatment with 40 mg of pravastatin daily or placebo. Five-year follow-up results showed a 24% reduction in coronary events, including death from CHD. A reduction was also noted in the need for percutaneous transluminal coronary angioplasty (PTCA) of 23% and coronary artery bypass graft (CABG) of 26%. Subgroup analysis showed that the magnitude of the benefit was proportional to the pretreatment LDL cholesterol level. Coronary events were reduced by 35% in patients who had pretreatment LDL cholesterol levels of 150 to 174 mg/dl, but patients with a pretreatment LDL cholesterol level of <125 mg/dl had no statistically significant reduction in cardiac events.

The AVERT trial (1999) compared the role of lipid-lowering drug therapy with PTCA in secondary prevention.^[19] Some 341 patients with stable CAD, LDL ≥115 mg/dl, and triglycerides ≤ 500 mg/dl were randomized to either aggressive lowering of LDL with atorvastatin (80 mg/d) or PTCA and usual care, which could include lipid-lowering therapy. High-risk patients were excluded if they had left main CAD, three-vessel CAD, ejection fraction < 40%, or recent MI or angina. Main outcome measures were ischemic events (including nonfatal MI, cardiac death, PTCA, CABG, or worsening angina requiring hospitalization), which were measured with intention-to-treat analysis at 18 months. The atorvastatin group had a reduced but not statistically significant rate of ischemic events (13.4% vs. 20.1%). This trial reassures that lipid-lowering therapy is safe and as good as PTCA for patients with stable CAD.

[edit] THE ROLE OF DIETARY INTERVENTION

The findings of the Oslo Study Group (1981) established the foundation for recommending dietary intervention and smoking cessation to improve lipid profiles.^[20] This prospective, multifactorial intervention trial was conducted among middle-aged men who had very high cholesterol levels (320 mg/dl), had high saturated fat consumption (mean 44% of daily caloric intake), and smoked. Dietary advice with cessation of smoking lowered total cholesterol by 13% and reduced the incidence of CHD by 47%. Generalization of the impact of these two findings is limited by the extreme cholesterol and fat intake of the enrolled subjects prior to the intervention. Other similarly designed trials have only been able to show a reduction in total cholesterol of 0% to 5% in patients with low total cholesterol levels and without CHD, and were unable to demonstrate statistically significant effects on CHD incidence.

The impact of dietary fish consumption was examined in a cohort of 1822 men from the Chicago Western Electric Study.^[21] The participants were 40 to 55 years old without known CHD; they were stratified into four groups based on fish consumption and followed prospectively for 30 years. Dietary consumption of fish (grams per day) was obtained from questionnaires at the onset of the study. Analysis of the data adjusted for demographics and other dietary factors revealed a significant inverse association between fish consumption and 30-year risk of death from all cardiovascular causes, especially non–sudden fatal myocardial infarction. The greatest protective effect was found in the participants who consumed 35 grams or more of fish per day. More recent evidence from the Physicians Health Study showed that men who ate fish (including shellfish) at least once a week had a 52% reduction of sudden cardiac death compared with those who consumed fish less than once per month.^[22] In contrast, these data did not find an inverse association between fish consumption and the rate of myocardial infarction. The protective mechanism of fish consumption is not yet known, but may be related to the effects of omega-3 fatty acids on cardiomyocyte membrane stabilization (see Nutritional Supplements).

[edit] AGE GROUPS TO SCREEN

The strongest evidence for screening asymptomatic patients was shown for men between the ages of 35 to 65 years. The age at which to screen women is controversial because of the lack of trial data in which adequate numbers were enrolled. The onset of clinically apparent CHD is dependent on multiple factors, but the beneficial effects of estrogen delay the incidence in women by a decade, and the risk increases progressively after menopause. Most authorities agree that an effective screening program for asymptomatic women should begin at 45 years of age or later. However, the NCEP II expert panel holds a minority view and advocates screening all adults (men and women) 20 years of age or older (Box 71-2).^{[23][24][25][9][26]}

Total cholesterol levels increase with age, most likely due to the proportional increase in the body mass index, and then plateau about age 65. Screening is less effective in patients after this age, especially if they have had a desirable lipid profile in their middle-aged years. Advocates of screening after this age point to the documented epidemiologic evidence that the risk of developing CHD is problematic until the age of 75. Most agree that elderly patients up to the age of 75 who have documented CHD will likely benefit from screening.

The appropriate interval for periodic screening has not been clearly defined. Five years is the standard presently proposed by the NCEP II for patients with desirable lipid profiles. Shorter intervals, in theory, would be more effective in perimenopausal women and in individuals with recent weight gain.

[edit] SCREENING FOR DYSLIPIDEMIA

A HDL cholesterol of less than 35 mg/dl is classified as a major risk factor and a level of 60 mg/dl or greater is considered a negative risk factor by the NCEP II. Screening for dyslipidemia by measuring total and HDL cholesterol compared with total cholesterol alone has not been proven to have additional benefit in the general population.^[23][25][26] However, it is helpful in identifying patients who will have the highest risk of developing CHD, especially when used to screen patients with other nonlipid risk factors for CHD.^[9] At present, total serum cholesterol and HDL cholesterol levels are recommended by the NCEP II for screening selected patients for primary prevention.

The higher the ratio of total-to-HDL cholesterol, the higher the risk of CHD.^[5] A ratio of five or greater is associated with increased CHD risk among men and women. Nonfasting samples are acceptable because recent consumption of a high-fat meal will have minimal effects on these two levels, unless the individual has high triglyceride levels.

[edit] PRINCIPLES OF MANAGEMENT

The combined CHD risk of a patient should be used as the guide to therapy. In primary prevention, this assessment takes into account LDL cholesterol level, a low or high HDL cholesterol level, age, cigarette smoking, diabetes mellitus, family history of CHD, and hypertension (Box 71-3).^[9] Those at higher risk of CHD should receive more aggressive intervention. Patients should be categorized into one of three groups according to risk: (1) highest risk—those with prior CHD or atherosclerotic disease, including peripheral arterial disease or symptomatic carotid disease; (2) high risk—those without CHD but multiple CHD risk factors; or (3) low risk—those with few CHD risk factors, especially men younger than 35 and premenopausal women.

The cornerstones of therapy for the patient with dyslipidemia include dietary counseling to reduce saturated and total fat consumption, weight loss, and drug therapy (if necessary). The possibility of adverse effects, as well as cost, warrants caution regarding the use of drug therapy in primary prevention for patients not at high risk. Cholesterol lowering through diet and physical activity is safer and should be the mainstay of therapy for primary prevention in most individuals.

Clinical trials have shown the strong benefit of lowering LDL cholesterol, but the evidence for raising HDL levels has only recently become elucidated. The VA-HIT study (1999) randomized 2531 men who were younger than 74 years old and had known CAD, low HDL levels (≤40 mg/dl), and moderate LDL (≤140 mg/dl) and triglyceride (≤300 mg/dl) levels.^[27] They were allocated to gemfibrozil (1200 mg/d) or placebo. The main outcome measures of nonfatal MI and death from CAD were significantly lower in the gemfibrozil-treated group (17.3% vs. 21.7%) over the median follow-up of 5.1 years. The evidence for using gemfibrozil over statins in men with CAD and low HDL levels has strengthened. However, the treatment of women with low HDL levels is likely to be similar, but has yet to be reported in a large clinical trial. Additionally low HDL levels should be treated with increased physical activity, smoking cessation, and weight loss. If a patient has concomitant high LDL and low HDL cholesterol levels, a drug that counteracts both should be prescribed.

[edit] Primary Prevention

In patients without CHD, the first step is to measure the serum total and HDL cholesterol levels (Table 71-3).^[9] Total cholesterol levels equal to or greater than 240 mg/dl are classified as high blood cholesterol and are the concentrations above which the risk for CHD is highest. A borderline high blood cholesterol concentration is a total cholesterol level between 200 and 239 mg/dl. Twenty percent and 31% of the U.S. adult population have levels within the high blood cholesterol and borderline high cholesterol categories, respectively.^[28] A desirable blood cholesterol concentration is defined as a total cholesterol level below 200 mg/dl.

Table 71-3 National Cholesterol Education Program Categories for Cholesterol Levels

✢Triglycerides in borderline high and very high categories may increase CHD risk. Levels greater than 1000 mg/dl are associated with increased risk of pancreatitis.

The second step, if required, is to perform a fasting lipoprotein analysis on all patients with a total cholesterol of 240 mg/dl or greater, or with a HDL cholesterol level lower than 35 mg/dl (Fig. 71-3). A lipoprotein profile includes measuring total cholesterol, HDL cholesterol, and triglycerides. The Friedewald formula is then used to calculate the LDL cholesterol:

Figure 71-3 Recommended advice and treatment for U.S. adults by cholesterol level. Shaded areas are the National Cholesterol Education Program's alternative recommendations for advice and treatment intensity. CHD, Coronary heart disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein. (Redrawn from Grundy SM, et al: Summary of the second report of the NCEP expert panel on detection, evaluation, and treatment of high blood cholesterol in adults, JAMA 269:3015-3023, 1993.)

LDL cholesterol = total cholesterol − HDL cholesterol

+ 0.16 (triglycerides)

This formula is valid for estimating LDL cholesterol if the triglyceride level is less than 400 mg/dl and if the individual does not have familial dysbetalipoproteinemia.

Further stratification is then based on LDL cholesterol levels. Three categories are used: high LDL cholesterol (levels equal to or greater than 160 mg/dl), borderline-high'LDL cholesterol (levels 130 to 159 mg/dl), and desirable LDL cholesterol (levels below 130 mg/dl).

If a patient has a desirable LDL cholesterol, the physician should educate the patient on the on the use of a low-saturated-fat diet, physical activity, and risk factor reduction. The patient should have a repeat total cholesterol and HDL cholesterol measured at 5 years. If the patient has a borderline-high LDL cholesterol with one or no risk factors, the same advice should be given but the patient should be reevaluated in 1 year.

If a patient has a borderline-high cholesterol level with two or more risk factors or a high-risk LDL cholesterol level, a careful clinical evaluation should then be performed. The aim of the clinical evaluation is to identify any secondary causes of hyperlipidemia by reviewing pertinent family history, present medications, and concomitant diseases. Testing for secondary causes, when indicated, should include thyroid-stimulating hormone (TSH) for hypothyroidism, serum glucose for uncontrolled diabetes mellitus, urinalysis and creatinine for nephrotic syndrome, and hepatic enzymes for liver disease. Active cholesterol lowering with dietary intervention should be instituted in all these patients. In addition, if a patient has a high-risk LDL cholesterol with two or more risk factors or an absolute LDL cholesterol greater than or equal to 190 mg/dl regardless of the presence or absence of risk factors, drug therapy should be instituted. The cholesterol levels at which dietary or drug therapy should be instituted are shown in Table 71-4.

Table 71-4 Treatment Guidelines Based on LDL Cholesterol Level and Risk Factor Status

[edit] Secondary Prevention

Secondary prevention begins with the fasting lipid analysis to determine the LDL cholesterol.^[9] The guidelines in these patients are much more stringent, and optimal LDL cholesterol levels are considered less than or equal to 100 mg/dl. Intervention for patients with LDL cholesterol levels above this value should begin with dietary modification. If the LDL cholesterol is greater than or equal to 130 mg/dl, drug therapy should not be delayed. With careful management, it is possible to achieve these goals within 3 to 6 months.

[edit] DIETARY THERAPY AND PHYSICAL ACTIVITY

The principal goal of dietary therapy is to lower an elevated serum cholesterol. The NCEP II expert panel has advocated dietary therapy that involves a two-step American Heart Association approach. The Step I diet consists of a daily cholesterol intake of less than 300 mg, as well as saturated and total fat consumption not to exceed 10% and 30% of total calories, respectively (Fig. 71-4). The Step II diet should be recommended to all patients with established CHD or patients who have not been able to achieve the targeted cholesterol level on a Step I diet. The goal of the Step II diet is to maintain saturated fat and cholesterol intake at a minimum by limiting daily intake of cholesterol to less than 200 mg and saturated fat to less than 7% of total calories.

Figure 71-4 Comparison of the Step I and Step II diets for lowering serum cholesterol. (Modified from Grundy SM, et al: Summary of the second report of the NCEP expert panel on detection, evaluation, and treatment of high blood cholesterol in adults, JAMA 269:3015-3023, 1993.)

A registered dietitian can be useful in helping patients with the difficult task of reducing their saturated fat and cholesterol intake, especially with the Step II diet. For the patient on the Step I diet, serum cholesterol levels should be monitored at 4 to 6 weeks and at 3 months following initiation of these changes. If the patient has achieved the targeted LDL cholesterol level, he or she can then be monitored with a total cholesterol measurement on a quarterly basis for the first year and biannually thereafter. At all visits, the primary care physician should reemphasize the adherence to diet and physical activity.

If the patient has not achieved the targeted cholesterol level on a Step I diet, the Step II diet should be prescribed. Total cholesterol levels should again be assessed at 4 to 6 weeks and at 3 months after instituting dietary therapy. If goals are achieved, monitoring as outlined above can begin. Otherwise drug therapy should be prescribed in addition to the Step II diet.

Aerobic exercise lowers total and LDL cholesterol and triglycerides, as well as increases HDL cholesterol. Exercise is also beneficial in decreasing a patient's weight toward ideal body weight. Weight reduction has been found to have benefits independent of exercise in improving dyslipidemia.

[edit] DRUG THERAPY

It is important to point out that even under the best of circumstances, rigorous nonpharmacologic therapy rarely yields more than a 10% to 15% reduction in total or LDL cholesterol. Physicians should apprise their patients of this likely outcome so that they do not become discouraged and choose to ignore the need to lower cholesterol levels. Clinical judgment is needed when patients have not met their target LDL cholesterol level by diet and physical activity, but do not meet the criteria for drug therapy. Patients with a low absolute risk of developing CHD but an abnormal cholesterol profile should be considered for delaying drug therapy. To illustrate this point, consider a 35-year-old premenopausal woman with a total cholesterol above 240 mg/dl, a LDL cholesterol greater than 160 mg/dl, and no family history of early CHD. Her CHD risk is higher than another 35-year-old woman with a normal cholesterol profile, but her absolute risk is still very small since she is unlikely to develop CHD for several decades. Nonpharmacologic interventions, including smoking cessation, diet, and physical activity, should be stressed to this patient. Low doses of bile acid sequestrants can be considered as an adjunctive therapy.

The major classes of drugs that reduce LDL cholesterol are HMG CoA reductase inhibitors, bile acid sequestrants, and nicotinic acid. Other classes of agents that have less of an effect on LDL cholesterol are fibric acid derivatives, probucol, and estrogen replacement therapy (Table 71-5). These will be discussed in turn.

Table 71-5 Lipid-modifying Drugs

[edit] HMG CoA Reductase Inhibitors (Statins)

As noted previously, large clinical trials have shown that lovastatin, pravastatin, and simvastatin reduce coronary events.^{[15][16][18][13]} Other trials have shown modest regression of coronary lesions with lovastatin, fluvastatin, pravastatin, and simvastatin.^{[29][30][31][32]} Lesion regression is likely less important than plaque stabilization. Recent data support this mechanism as a means to explain the reduction in acute clinical CHD events associated with the use of these drugs. These benefits are considered a class effect and are believed to carry over to the other statins.

As a group, the statins lower total cholesterol, LDL cholesterol, VLDL cholesterol, and triglycerides. They may also mildly increase HDL cholesterol. The efficiency of lowering LDL cholesterol, cost, and hepatic CYP3A4(P450) metabolism appear to be the basis for differences among the statins. Maximum daily doses of cerivastatin (0.3 mg), lovastatin (80 mg), pravastatin (40 mg), and simvastatin (40 mg) reduce LDL cholesterol by 30% to 40% when compared with the 25% reduction by fluvastatin (40 mg). Atorvastatin at maximum dosage (80 mg) has been reported to reduce LDL cholesterol by as much as 50% to 60%.^[33]

The initial dose should be low and titrated every 4 to 6 weeks until the desired target LDL cholesterol is achieved. Typical dosing is once daily, and these agents are most efficacious when taken with the evening meal to reduce nocturnal hepatic synthesis of cholesterol.

The most common side effects include rash, headache, gastrointestinal distress, and myalgias. Patients with concomitant renal or hepatic dysfunction, hypothyroidism, advancing age, and bacteremia appear to have an increased risk of myalgias and myositis. If severe enough, myositis can lead to rhabdomyolysis, myoglobinemia, and acute renal failure. Myositis associated with an increase in serum creatine phosphokinase levels up to 10 times normal is reversible after discontinuation of the drug. Increases in hepatic transaminases may occur in 1% to 2% of patients taking higher doses of statins. Some lipid experts recommend obtaining hepatic transaminase measurements at 6-week intervals until a stable dose of the statin has been achieved. Thereafter, testing is recommended at 6-month intervals. A rare lupus-like syndrome and peripheral neuropathy have been reported with statin use.

Because statins are one of the newer classes of lipid-lowering drugs, their long-term sequelae are not known. At present, there are little data to suspect any long-term adverse outcomes. Despite higher cost, statins have proven effectiveness and good patient acceptability, making them the first choice for most patients with hypercholesterolemia.

[edit] Bile Acid Sequestrants

The bile acid sequestrants, cholestyramine and colestipol, bind bile acids and prevent their absorption in the ileum. The bile acids, including cholic and chenodeoxycholic acid, are derivatives of cholesterol. The depletion of the bile acid pool results in feedback to the hepatocytes to increase expression of LDL cholesterol receptors to enhance hepatic uptake of LDL. The net effect of bile acid sequestrants is to lower LDL cholesterol by increasing its catabolism.

Cholestyramine and colestipol lower LDL cholesterol by 15% to 30%, increase HDL cholesterol by 3% to 8%, but increase triglycerides by 10% to 50%. The effective dose is 2 to 6 packets or scoops per day (8 to 24 grams daily). Both drugs have nonlinear dose-response curves so that maximal doses of these agents have little additional benefit, but side effects increase proportionally. The main side effects are largely limited to gastrointestinal distress, including heartburn, bloating, constipation, and exacerbation of preexisting hemorrhoids or anal fissures. Adding fiber to the diet will improve constipation, and letting the resin stand in liquid before consumption will alleviate heartburn. Treatment should begin with two to four scoops per day as an initial dose, and the drug should be taken with meals to reduce side effects. Patients should be advised to take these resins separately from any other oral medications because they may bind to the resin and not be absorbed. The most important of these are digoxin, thyroxine, thiazide diuretics, β-blockers, and warfarin. A period of 1 hour before or 4 hours after taking oral medications should be allowed before a resin is consumed.

Because of their rather benign side effect profile, bile acid sequestrants are considered by the NCEP II expert panel to be a good choice for young patients who will be taking cholesterol-lowering therapy for decades. Similar recommendations apply to women of childbearing age.

[edit] Niacin

Nicotinic acid or niacin is a member of the B complex family of vitamins, but at higher doses also lowers cholesterol and is therefore classified as a drug. It is, however, available over-the-counter because the Food and Drug Administration (FDA) classifies it as a vitamin. Niacin lowers total and LDL cholesterol by 10% to 25% and triglycerides by 20% to 50%, and increases HDL cholesterol by 15% to 30%. Niacin is considered a very effective treatment for low HDL cholesterol and for the treatment of small, dense LDL (see Controversies and Future Considerations). The exact mechanism of action is not known, but it is thought to decrease the production of VLDL and LDL. The mechanism by which niacin increases HDL cholesterol is also not known.

Initiation of niacin therapy should begin with low doses of 50 to 100 mg BID to TID with meals. Niacin is available in regular-release and time-release capsules. The newer time-release agents have promoted increased patient acceptability. The dose is then increased over a period of 6 to 8 weeks to 1500 mg daily, and should be adjusted depending on the initial response of the cholesterol level. The usual effective dose is 1500 to 3000 mg daily in three divided doses.

The major side effect is flushing, and this unpleasant reaction often hampers patient compliance. Administration of 325 mg of aspirin 30 minutes before the administration of niacin and the avoidance of hot liquids and alcohol minimize or prevent most flushing episodes. Physiologic tolerance to this side effect eventually develops. Only after patients have developed tolerance at a specific dose should niacin therapy be increased.

Other side effects include pruritus, which may be ameliorated with antihistamines; rash; body odor; gastrointestinal distress; and exacerbations of gout. If the patient has concomitant diabetes mellitus, the physician should be aware of the possibility of worsening glycemic control. There is also dose-dependent hepatotoxicity, especially with the time-release capsules, termed niacin hepatitis.

Some key features of this uncommon disorder include a history of malaise, hepatomegaly, and elevated transaminases. Fortunately, the hepatitis begins to reverse within days of decreasing or stopping the drug, and this observation has led some lipid experts to recommend not exceeding 2000 mg daily.

[edit] Fibric Acid Derivatives

Fibric acid derivatives decrease hepatic VLDL synthesis and increase the effectiveness of VLDL and triglyceride removal from the circulation. Owing to the lower concentrations of circulating VLDL, there is less cholesterol to be transferred from HDL to VLDL. The net effect is that they are the most effective drugs for reducing triglyceride levels, with a subsequent HDL increase of approximately 10%. The effect on LDL cholesterol is variable and dependent on the initial level of triglycerides. In patients with very high triglyceride levels, the lowering of triglycerides may actually increase the LDL cholesterol level.

The fibric acid derivatives provide the most benefit in lowering CHD risk in patients with hypertriglyceridemia (including diabetics), combined hyperlipidemia, and familial dysbetalipoproteinemia. These agents are not effective in patients with isolated hypercholesterolemia.

Clofibrate was the first drug of this class to have been prescribed. A 1992 study that compared clofibrate with placebo found a higher incidence of cancer as well as other gastrointestinal diseases, including cholecystitis and gallstones requiring cholecystectomy, among patients treated with clofibrate.^[34] This drug has since fallen out of favor and has been superseded by the use of gemfibrozil and the newest fibric acid derivative available in the United States, micronized fenofibrate.

Gemfibrozil is considered a safe drug on the basis of lengthy experience in the Helsinki Heart Study.^[11] The recommended dose is 300 to 600 mg twice daily. Micronized fenofibrate (67 mg) is equivalent to the 100 mg of the nonmicronized form available in Europe and Canada. An equivalent dose of 200 to 400 mg daily is recommended. Micronized fenofibrate appears to be more effective in lowering triglycerides with a more favorable effect on LDL cholesterol levels than gemfibrozil.^[35]

The main side effects of the fibrates include abdominal pain, nausea, diarrhea, rash, and pruritus. Transient elevations in hepatic transaminases have been noted. These drugs are conjugated in the liver and excreted in the urine, making them relatively contraindicated in hepatic or renal disease. As with clofibrate, the fibric acid derivatives as a class appear to increase the long-term risk of cholelithiasis.

[edit] Probucol

Probucol is a unique agent for the treatment of dyslipidemia whose mechanism of action is not fully understood. Proposed actions include removing LDL from the circulation by increased efficiency of LDL receptor binding and increased non–receptor-mediated catabolism of LDL. Probucol is also a highly effective antioxidant. While it lowers LDL by 10% to 20%, the drug also lowers HDL, leading to a neutral effect on the total-to-HDL cholesterol ratio. The usual dosage is 500 mg twice daily. Side effects are mostly limited to gastrointestinal distress. It is contraindicated in any patient with a prolonged QT interval or a history of ventricular dysrhythmias. Despite being on the market for over 2 decades, its role in lipid management is limited, largely owing to its adverse effects on HDL cholesterol. Its benefits as an antioxidant, however, may prove to modify and expand its use in the future.

[edit] Estrogen Replacement Therapy

A major question in the treatment of postmenopausal women with lipid disorders is the efficacy of estrogen replacement therapy, either alone or in combination with other lipid-lowering drugs. Clinical trials of large magnitude have yet to be performed, but a meta-analysis of some observational studies suggests a reduction of approximately 44% in the primary prevention of CHD risk by estrogen replacement therapy.^[36] The NCEP II expert panel recommends estrogen replacement to all postmenopausal women with lipid disorders. This recommendation is controversial because there are incomplete data to support this stance.

Framingham Study data suggested a fourfold increase in CHD risk for women who experience menopause before 40 years of age.^[37] They also noted that the risk of CHD increases twofold in women who underwent natural menopause in their sixth decade. There is agreement that CHD risk increases with age for both women and men, and that premature ovarian failure is associated with increased risk. The contribution of ovarian failure to CHD risk in women who undergo natural menopause is controversial. Benefit has yet to be proven in this population of women.

Estrogen replacement benefits the lipid profile by decreasing LDL and lipoprotein(a), and increasing HDL. However, triglycerides are also increased. The initial studies of estrogen replacement therapy used this therapy without progestins in women with an intact uterus. Current practice dictates prescribing progestins in women with an intact uterus because it is now known that estrogen therapy used in an unopposed manner increases the risk of endometrial cancer approximately sixfold. There is also an increase in the risk of deep vein thrombosis, pulmonary embolism, and possibly breast cancer with hormone replacement therapy (HRT).

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial (1995) examined risk factor changes (HDL cholesterol, systolic blood pressure, serum insulin, and fibrinogen) as a surrogate marker for CHD events.^[38] Combined estrogen/progestin therapy had a less desirable effect on HDL cholesterol than estrogen therapy alone. This has led some authorities to believe that combined therapy will not be as effective in lowering CHD risk. Proponents of estrogen replacement estimate that the effect of estrogen on lipids only accounts for about one third of its beneficial effect on CHD risk. Other cardiovascular benefits of estrogen include increased levels of nitric oxide, which allow less spasm of the coronary vasculature; increased insulin sensitivity; and its role as a possible antioxidant.^[39]

The Heart and Estrogen/Progestin Replacement Study (HERS) (1998) randomized 2763 postmenopausal women with established CHD to either conjugated equine estrogen (0.625 mg/d) and medroxyprogesterone acetate (2.5 mg/d) or placebo.^[40] After a mean follow-up of 4.1 years, the rate of nonfatal myocardial infarction and CHD mortality did not differ between the women who received HRT (12.5%) and those who received placebo (12.7%), despite significant improvements in LDL, HDL, and triglycerides in the HRT-treated group. From these results, some authorities are advocating the use of proven secondary prevention measures of lowering CHD risk (including other lipid-lowering agents) more strongly than HRT therapy.

The role of HRT in primary prevention will hopefully be evaluated by the ongoing Women's Health Initiative clinical trial. This study is attempting to recruit 27,500 women and to randomize them to either combined estrogen/progestin therapy or placebo if they have an intact uterus. If they had a hysterectomy, they will be treated with estrogen alone. The investigators plan to observe the response to treatment over 9 years, with results reported in the year 2005. Hopefully this trial and others to follow will elucidate the effect of progestin in combination with estrogen replacement therapy.

[edit] Other Drugs

Raloxifene is a nonsteroidal benzothiopene that inhibits the growth of estrogen receptor–dependent mammary tumors. It is classified as a selective estrogen-receptor modulator that has shown to be efficacious in preventing bone loss, having a less stimulatory effect on the endometrium compared with estrogen, and to lower serum total cholesterol and LDL cholesterol. Raloxifene has also been shown to decrease LDL oxidation, decrease vascular smooth muscle migration, and decrease restenosis in animal models. A recent study of 601 postmenopausal women who were randomized to receive 30, 60, or 150 mg of raloxifene daily or placebo daily were followed for 2 years.^[41] Both groups also received 400 to 600 mg elemental calcium daily. In addition to improvements in bone mineral density, raloxifene was shown to have a dose-dependent reduction of serum concentrations of total cholesterol and LDL cholesterol of 9.7% and 14.1% respectively, in the group treated with raloxifene, 150 mg daily. Serum concentrations of HDL and triglycerides were not significantly different from placebo. Smaller studies have shown a trend for raloxifene decreasing lipoprotein(a) and apo B levels. Raloxifene may be found useful in the treatment of certain postmenopausal women with elevated levels of total cholesterol and LDL cholesterol with less risk of estrogen's stimulatory effect on mammary and endometrial tissue. Low HDL levels are, however, best improved with estrogen replacement in conjunction with exercise.

D-thyroxine lowers LDL cholesterol by 10% to 15% by enhancing its clearance from the circulation. This treatment makes the patient mildly hyperthyroid, and has been essentially abandoned because of the cardiac side effects. Neomycin decreases intestinal absorption of cholesterol when given in a dosage of 2 grams daily; it can lower LDL by 10% to 15%. Besides altering the native gut flora, neomycin has the potential to cause ototoxicity and renal insufficiency, and has not been approved by the FDA as a lipid-lowering agent. Olestra is a nonabsorbable sucrose polyester fat substitute that interferes with the absorption of cholesterol and fat-soluble vitamins by solubilizing cholesterol, making it unavailable for intestinal absorption. It is approved by the FDA for use in foods, but not as a drug.

Stanols and their saturated derivative sterols structurally resemble cholesterol except for the addition of a methyl or ethyl group. They are found exclusively in plants and are important for cellular membrane integrity. When dietary intake of plant sterols and stanols is higher than typical daily intake, they compete with cholesterol in the formation of mixed micelles and interfere with cholesterol absorption in the gastrointestinal tract. Evidence for this effect has been shown in several studies over the last 40 years.^[42] Sitostanol-ester margarine is a pine tree–extract stanol that is esterified to allow solubilization in a low-saturated-fat vehicle (e.g., margarine). The RAISIO Group (1995) in Finland studied 153 nonobese subjects with mild dyslipidemia (total cholesterol levels greater than 216 mg/dl, triglycerides less than 265 mg/dl).^[43] They were randomized to either sitostanol-ester margarine or placebo margarine. After 1 year, the sitostanol-ester group had a significant reduction of total cholesterol (10.2%) and LDL cholesterol (14.1%), and the agent was well tolerated. There was no significant difference in triglyceride or HDL cholesterol levels between the two groups. Sitostanol-ester margarine has recently been approved to be marketed in the United States, but its role has yet to be determined in the treatment of dyslipidemia.

[edit] Combination Therapy

The goal of combination therapy is to combine lipid-lowering drugs of different mechanisms of action in order to achieve an additive or synergistic therapeutic effect in patients with dyslipidemia.^[44] In patients with severe dyslipidemia, such as familial hypercholesterolemia and familial combined hyperlipidemia, the use of combination therapy may be required to reach target LDL cholesterol levels (see Table 71-2).^[45] Combination therapy has also proven useful in patients with less severe forms of dyslipidemia by using low doses of two agents rather than a high dose of a single agent. Not only may there be a potential decrease in clinical toxicity with combination therapy, but there also may be a cost advantage.

The bile acid sequestrants (cholestyramine and colestipol) are the most commonly used agents included in combination therapy. The benefits of these drugs are that they are not absorbed and have less drug interactions than their counterparts. Bile acid sequestrants have been shown to be efficacious in combination with nicotinic acid, the statins, the fibrates, and probucol. However, the most effective regimens have been bile acid sequestrants in combination with nicotinic acid or the statins. Nicotinic acid (4.5 to 5.5 grams/day) when combined with the full dose of a bile acid sequestrant can achieve a 32% to 55% reduction of LDL cholesterol, but it is poorly tolerated because of cutaneous flushing and gastrointestinal side effects. In addition to good tolerability, LDL cholesterol reductions of over 50% are commonly achieved with a bile acid sequestrant in combination with a statin, making them ideal drugs for combination therapy. Bile acid sequestrants should be taken at least 1 hour prior to the administration of a statin because of its ability to bind to a statin and make a statin less available for absorption. The combination of lovastatin, colestipol, and nicotinic acid has been shown in a limited number of studies of patients with severe dyslipidemia to lower LDL cholesterol by 60% to 70%.

Statins in combination with a fibric acid derivative have been reported to increase the risk of myositis more than that of statin therapy alone.^[46] These two drugs should, in general, not be prescribed together. However, on occasion their combined use may be necessary for patients who are resistant to other forms of drug therapy.

[edit] PATIENT EDUCATION

The importance of the physician's role as patient educator cannot be overemphasized in the management of CHD risk. An interactive environment should be established, with the underlying theme being that the patient is an important participant in maintaining his or her wellness. Expecting patients to be compliant with a prescribed regimen without proper education will result in frustrations for both physician and patient. One study demonstrated that only approximately 50% of patients who were prescribed a lipid-lowering drug were taking it 1 year later.^[47] In another study, 20% to 30% of women never filled their prescription for HRT, and only about 40% who did were still compliant with the regimen 1 year later.^[48] One of the more commonly cited reasons for noncompliance was that the patients did not understand why they needed to be on the medication.

Compliance may be increased by reviewing the basics of dietary reduction of saturated fat and cholesterol and weight reduction at periodic visits. Since dietary therapy cannot be expected to reduce LDL by more than 10%, it is important to be nonjudgmental if a higher and unrealistic goal was initially established. Asking the patient his or her understanding about prescribed therapy may also curtail noncompliance and increase patient satisfaction.

[edit] CONTROVERSIES AND FUTURE CONSIDERATIONS

[edit] Hypertriglyceridemia

The role of elevated triglycerides in CHD risk has been more controversial than the association of high LDL cholesterol and low HDL cholesterol. Large studies initially linked elevated triglyceride levels with CHD. Subsequently, when HDL cholesterol levels were measured with triglyceride levels, elevated triglycerides were often found to coexist with low HDL cholesterol levels, and were not initially found to confer an independent CHD risk.^[49] This observation led to the early conclusion that hypertriglyceridemia is not an independent risk factor for CHD, and that HDL cholesterol is the principal risk factor determinant. More recently, however, individuals with low HDL cholesterol and elevated triglyceride levels have been found to have a greater CHD risk than individuals with similarly low HDL cholesterol but normal triglyceride levels.^[50][51] This type of observation gives some credibility to the independent association of elevated triglyceride levels and CHD risk, but that association appears to be less robust than that for low HDL cholesterol.

Nonpharmacologic therapy (weight reduction, increased physical activity, and alcohol restriction) is recommended for all patients with elevated triglycerides (200 mg/dl or greater).^[9] There has yet to be conducted a clinical trial to establish a benefit, if any, of lowering triglyceride levels and improved CHD risk. Until intervention data are available, triglyceride-lowering agents should be reserved for patients with triglyceride levels of 400 mg/dl or greater and other cardiac risk factors.^[52]

[edit] Small, Dense LDL and the Atherogenic Dyslipidemia Syndrome

LDL can be divided into four subclasses with differing density, size, and atherogenic risk. The largest, most buoyant subclass is LDL-I, followed in decreasing size and buoyancy by LDL-II, LDL-III, and LDL-IV. LDL-I and LDL-II subclasses are seen predominantly in patients with normolipidemic profiles and have been termed pattern A. LDL-III and LDL-IV as a group have been termed pattern B, also denoted as small, dense LDL particles.

The atherogenic dyslipidemia syndrome (ADS) includes the clustering of four different abnormalities: borderline high total cholesterol; high triglycerides; small, dense LDL particles (pattern B); and low levels of HDL cholesterol.^[10][53] ADS is a dominant dyslipidemia and has been found in patients with CHD and familial combined hyperlipidemia. The lipid profile of ADS is similar to that of patients with type II diabetes mellitus, and it has been suggested that ADS is a risk factor for the development of type II diabetes mellitus. ADS in combination with type II diabetes mellitus, hypertension, central obesity, and a procoagulant state has been termed syndrome X or the metabolic syndrome. The morbidity associated with this metabolic derangement of proatherosclerotic risk factors is just beginning to become elucidated.

ADS is associated with at least a threefold increased risk of CHD.^[54] The relative contribution of each of the four components to CHD risk is unclear because they usually coexist and separation of their individual risk has been unsuccessful.^[10] In addition to what has been already suggested with hypertriglyceridemia, small, dense LDL may also be an independent CHD risk factor.✢✢References^[55], ^[56],^[57], ^[58],^[10], ^[53][59], ^[60]At present, the estimation of CHD risk is determined from the level of HDL and the ratio of total cholesterol-to-HDL cholesterol. In the future, triglycerides or small, dense LDL may be added to this analysis in order to increase the predictive power of the risk assessment.

Standard screening with total cholesterol and HDL cholesterol is not adequate for the identification of patients with ADS because the resulting “normal” lipid profile will overlook this atherogenic disorder.^[10] The present challenge for primary care physicians in diagnosing ADS is to identify those patients at risk for premature CHD, or those with established CHD and seemingly “normal” lipid profiles. Future testing may include routine measurement of the various subclasses of lipoproteins including small, dense LDL. At present, this cannot be recommended until there is standardization of the laboratory measurement of lipoprotein subclasses.

Therapy is based on diet, exercise, and drug treatment. A subgroup of patients from the Helsinki Heart Study with ADS (pattern B), when compared with patients with pattern A, had a significant reduction of CHD events. Gemfibrozil-treated patients with ADS had increased levels of large LDL and decreased levels of small, dense LDL; gemfibrozil had no significant effect on pattern A subjects. The striking feature of this observation is that drug treatment improved the lipid profile of the pattern B patients, an effect that would not have been revealed by routine lipoprotein monitoring. Lipid experts believe there is no one ideal drug with which to treat this disorder; however, since ADS represents a combination of metabolic derangements, some combination of nicotinic acid, statins, and fibric acid derivatives may be effective.^[10]

[edit] Hyperapobetalipoproteinemia (Hyperapo B)

Apolipoprotein B (apo B) is the component of LDL that serves as the ligand for its receptor. Apo B is also contained within VLDL, IDL, and chylomicrons. There is only one molecule of apo B in each of these lipoprotein particles. Therefore measuring fasting serum apo B should correlate on a 1:1 ratio with the total number of VLDL, LDL, IDL, and chylomicron particles.^[61]

An increased apo B level in the absence of hyperlipidemia has been designated hyperapo B, which is found in hypertriglyceridemia.^[62][63] Persistently elevated triglycerides replace the cholesteryl ester component of VLDL and LDL, while the apo B levels remain the same. When this occurs, the apo B level is a more accurate representation of the total number of VLDL and LDL particles as compared with the cholesterol measurement because the risk of CHD is greater than indicated by the measured cholesterol level.^[62][64] Hyperapo B often accompanies ADS, but is not necessarily a component thereof.^[10]

Some recommendations for assessing CHD risk include the quantification of apo B in patients who have a family history of premature CHD, and patients with documented CHD who do not require lipid-lowering therapy based on the current NCEP II guidelines. Analysis of some clinical trials has recognized that apo B is a strong predictor of CHD risk, and that reduction of apo B lowers CHD.✢✢References ^[65],^[66], ^[67],^[68], ^[69],^[70], ^[71].Prospective studies are needed to determine if apo B is a better predictor of CHD risk than the current lipid measurements.

[edit] Lipoprotein(a)

Lipoprotein(a) or Lp(a), is a unique particle that contains a LDL component and a unique covalently linked protein component, apoprotein(a). Apo(a) is linked by a disulfide bridge to apo B-100 of the LDL component, and its structure is similar to that of plasminogen. The atherogenic potential of Lp(a) has been attributed to its competition with plasminogen for the plasminogen receptor on endothelial cells and for fibrin, thereby reducing fibrinolysis and promoting thrombosis.^[72] Lp(a) is considered an independent risk factor for premature CHD, but its importance appears to lessen with advancing age.^[73][74] Elevated Lp(a) levels are not always associated with increased CHD risk owing to variability within the apo(a) molecule allowing for some polymorphisms to have increased risk. The precise relationship between apo(a) structure and sequence and CHD risk is the subject of ongoing studies.

Levels of Lp(a) are genetically determined, but external factors may account for up to 10% of the variation in concentration. Renal impairment and nephrotic syndrome are among the best studied nongenetic factors. An inverse correlation exists between Lp(a) and creatinine clearance that may account for the greater prevalence of CHD in this population.^[75] Genetic determinants of Lp(a) levels may cluster in certain ethnic groups. African-Americans have higher Lp(a) levels and Asians have lower Lp(a) levels when compared with the general U.S. population; yet, among the African-American population, the risk associated with any given level of Lp(a) is less clear than among Caucasians likely as a consequence of polymorphic differences in apo(a).^{[76][77][78][79][80][81]}

Despite controversy, screening for Lp(a) has been recommended by some lipid experts to be measured in individuals with a family history of premature CHD, or in individuals with established premature CHD and a low risk factor profile with relatively normal lipid levels.^[74] Treatment with niacin or neomycin has been shown to be effective in lowering Lp(a) levels. However, there have been no trials to support the view that lowering Lp(a) levels reduces CHD risk. In the future, Lp(a) may become an integral measurement of CHD risk, but not until we standardize its measurement, better define the isoforms and polymorphisms that confer the greatest risk, and more fully understand its impact on the development of atherosclerosis.^[82]

[edit] Diabetes Mellitus

CHD is the principal cause of death in patients with diabetes mellitus. Subgroup analyses of secondary prevention trials of statin therapy indicate that lowering LDL levels in patients with diabetes mellitus is beneficial.^[16][18] It is not clear if the target of therapy is the same as in the general population. Unanswered questions include whether the LDL goal of less than 100 mg/dl in diabetics with CHD should be further lowered. Also, we do not know how aggressively to treat patients with diabetes mellitus and no known CHD. There have as yet been no large clinical trials to answer these questions. At present, the NCEP II recommends a target LDL of 130 mg/dl for primary prevention, and less than 100 mg/dl for secondary prevention. Triglycerides are also an important risk factor in patients with diabetes, and it has been suggested that a level of less than 200 mg/dl be the goal. However, for those patients with established CHD or vascular disease, a triglyceride level of less than 150 mg/dl should be the goal.^[83] Future trials will hopefully define the optimal approach to lipid-lowering therapy in patients with diabetes mellitus.

[edit] Cerebrovascular Disease

The role of dyslipidemia in cerebrovascular disease (stroke and transient ischemic attack [TIA]) is not well understood. CHD and stroke share many of the same risk factors including age, sex, blood pressure, preexisting vascular disease, diabetes mellitus, and smoking. A notable difference is dyslipidemia. Large population-based studies prior to the advent of computed tomography grouped cardioembolic, atherothrombotic, and hemorrhagic strokes together, which created conflicting data in the understanding of dyslipidemia and its association with stroke. Another difficulty has been the methodologic flaw in the design of studies, which predominantly looked at CHD as the endpoint. Cerebrovascular events only occurred in a small number of individuals in these studies because their incidence is delayed about 1 decade in respect to CHD.^[84] There have been no large trials looking at all forms of cerebrovascular disease as an endpoint; however, secondary analysis of data from the CARE and the 4S trials has found a significant reduction in stroke among patients treated with statins. A systemic review of 16 trials using statin therapy found a 25% reduction in all forms of stroke when total cholesterol and LDL cholesterol were reduced 22% and 30% respectively.^[85] In a case-controlled study of 90 patients with atherothrombotic stroke or TIA, subjects were found to have significantly higher levels of total cholesterol, LDL cholesterol, and triglycerides than a matched control group.^[86]

These insights suggest that dyslipidemia is associated only with atheroembolic stroke. The attributable risk of dyslipidemia to stroke may be reduced after significant reductions of total cholesterol and LDL cholesterol with prolonged statin therapy. Clinical studies are needed that will improve our understanding of the interaction of dyslipidemia with this heterogeneous disorder.

[edit] Alcohol

Studies have shown that alcohol in moderation protects against CHD. A prospective study of 490,000 men and women found that participants who averaged one drink per day had a 21% decrease in all-cause mortality and a 30% to 40% decrease in mortality from CHD.^[87] Another study found that men who drink moderate amounts of alcohol (two to six drinks per week) have a 28% reduction in all-cause mortality compared with light drinkers (one or fewer drinks per week).^[88] The protective effect of moderate drinking was attributed to a 34% to 53% reduction in CHD mortality. However, when heavy drinkers (two drinks or greater per day) were compared with the light drinkers, they were found to have a 51% increase in all-cause mortality.

Alcohol consumption is directly proportional to HDL and triglyceride levels. The greatest consumers of alcohol have both the highest levels of HDL and of triglycerides when compared with minimal consumers. However, a U-shaped association between alcohol consumption and CHD risk has been defined. Despite the elevated levels of HDL in the highest consumers of alcohol, the role of hypertriglyceridemia or some other unknown factor may have a greater adverse effect on CHD risk. Alcohol consumption appears to have no effect on LDL levels.

Recent data from the Helsinki Heart Study have shown that the beneficial effect of moderate alcohol consumption may be restricted to tobacco smokers only.^[89] Future studies may clarify which subgroups of the population may benefit from moderate alcohol consumption. However, the current recommendation of the American Heart Association limits the health benefit of alcohol to one to two drinks per day.^[90]

[edit] Nutritional Supplements

Epidemiologic data have suggested that there is a lowered prevalence of CHD in populations with a higher intake of fruits and vegetables. There is also a widespread belief that antioxidant vitamins (vitamins C and E) will reduce the risk of CHD. This premise is based on the belief that since LDL oxidation promotes atherogenesis, impairing oxidation should reduce CHD risk. However, the GISSI-Prevenzione trial (1999) showed vitamin E supplementation to have a neutral effect.^[91] This secondary prevention study randomized 11,324 patients who had suffered a recent myocardial infarction (within 3 months) to either dietary supplementation with omega-3 PUFAs (eicosapentaenoil acid, 850 mg, and decosahexaenoic acid, 1700 mg) or vitamin E (α-tocopherol, 300 mg), singly or in combination. Intention-to-treat analysis at 42 months revealed a significant reduction of nonfatal MI and cardiovascular death, in addition to all-cause death and stroke, in the omega-3 PUFA-treated group. Supplementation with vitamin E alone or in combination showed no effect. The more recent HOPE study (2000) did not find any discernible effect of vitamin E (400 IU/d) on cardiovascular events in subjects with CAD or diabetes mellitus over a duration of 4.5 years.^[92] These large clinical trials add to the strong but limited body of evidence of the beneficial effects of omega-3 PUFAs and the mixed results of vitamin E supplementation.^[93][94][95] Folic acid and vitamin B₆ are also thought to be beneficial in decreasing CHD risk by reducing elevated homocysteine levels, another known atherogenic factor. It is not clear whether folic acid and vitamin B₆ supplementation reduces the risk of CHD.^[96]

Most of these current beliefs have yet to be proven by large clinical trials. In the future, nutritional prevention may expand to include these factors along with weight loss and reduced intake of saturated fat and cholesterol.

[edit] SUMMARY

The prevalence of CHD will continue to increase because more people will be living longer with CHD. A reduction in the prevalence of CHD in this new cen